The random screening of molecules for their possible activity as therapeutic agents has been being done for many years, as a consequence of which a number of important drugs have been discovered. Recently, non-peptide compounds have been developed which mimic the secondary structure of reverse-turns found in biologically active proteins or peptides. For example, U.S. Pat. No. 5,440,013, and Published PCT Application Nos. WO 94/003494A1, WO 01/000210A1, and WO 01/016135A2, all to Kahn, each disclose conformationally constrained non-peptide compounds, which mimic the secondary structure of reverse-turns. In addition, U.S. Pat. Nos. 5,929,237 and 6,013,458 that is a continuation-in-part (CIP) thereof, both to Kahn, describe conformationally constrained compounds which mimic the secondary structure of reverse-turn regions of biologically active peptides and proteins. The synthesis and identification of conformationally constrained reverse-turn mimetics and the application thereof to diseases were reviewed by Obrecht (Advances in Med. Chem., 4, 1-68, 1999).
As mentioned above, significant advancements have been made in the synthesis and identification of conformationally constrained reverse-turn mimetics, and techniques have been developed and provided that synthesize and screen library members of small molecules which mimic the secondary structure of peptides, in order to identify bioactive library members. Accordingly, attempts have been made to seek conformationally constrained compounds and highly bioactive compounds which mimic the secondary structure of the reverse-turn regions of biologically active peptides and proteins. For instance, reverse-turn mimetics, methods of manufacturing the same and bioactivities thereof are disclosed in PCT Application Nos. WO 04/093828A2, WO 05/116032A2, and WO 07/139,346A1.
Although a great number of the reverse-turn mimetics mentioned above have been manufactured, efforts continue to be made to manufacture compounds applicable to the treatment of diseases such as cancer, etc.
Of particular mention is the effort that has been focused on the development of compounds which strongly block a Wnt signaling pathway to effectively suppress the growth of acute myeloid leukemia (AML) cancer cells which are known to have an activated Wnt signaling pathway.
Also, there is a need to develop methods of manufacturing highly bioactive compounds on a mass scale once they have been found.